Schema unification and morphological productivity: A diachronic perspective

Unified schemas which allow for deriving multiply complex word-formation products are a central concept in Construction Morphology (CxM). Based on examples such as un-V-able formations in English, Booij (2007: 38) argues that unified schemas (in this case: [un[Vable] A]A) can be conceived of as “short cuts in coining new complex words”. In this paper, we explore three prospective cases of schema unification and discuss what kind of evidence supports the assumption of unified schemas. The first two case studies are diachronic in nature. Drawing on corpus analyses of data from the Early New High German period (1350−1650) and from the early stages of New High German, we show how the developments of the complex patterns diverge from the developments of their counterparts. To this end, we analyze the frequency and productivity of the (sub-)constructions and assess the semantics of the word-formation products. Firstly, nominalization with the suffix -ung has been shown to undergo a diachronic decrease in morphological productivity (Demske 2000; Hartmann 2016). However, unified schemas such as [Be-X-ung]N or [(PREF)-X-ierung]N are shown to be still productive, e.g. Beplankung, Belaberung, Vercomedianisierung (from www.wortwarte.de, a collection of neologisms). In a similar vein, complex derivation of the type [un-V-lich]ADJ ‘un-V-able’ is shown to have remained productive for a longer period of time than its simplex parent schema [un-V-lich]ADJ. Moreover, many un-V-lich derivatives historically precede their unprefixed counterparts, or lack them altogether (unwiderstehlich ‘irresistible’, but *widerstehlich). Our third case study explores present day German pseudoparticiples (bebrillt ‘bespectacled’) using web data. The complex pattern can be shown to diverge stylistically from its parents schemas and also to provide semantically more uniform derivatives. Overall, our results show that the concept of unified schemas can help explain important differences in the development of the individual subpatterns in terms of morphological productivity and in terms of semantic aspects of the word-formation constructions

Validierung der Herstellung und Qualitätsprüfung autologer dendritischer Zellen für die adjuvante Immuntherapie

Am Institut für Klinische Hämostaseologie und Transfusionsmedizin der Universität des Saarlandes wurde 2012 ein Forschungsprojekt initiiert, um die Herstellungserlaubnis für dendritische Zellen zur adjuvanten Immuntherapie von höhergradigen Gliomen zu erlangen. Gliome sind die häufigsten primären Hirntumore, wobei die höhergradig-malignen Glioblastome unter diesen den größten Anteil ausmachen. Die Standardtherapie dieser Tumorentität ist die Kombination aus Operation und Radiochemotherapie. Unter dieser Therapie liegt die mittlere Überlebenszeit der Patienten bei 14,6 Monaten. Auf Grund der nicht zufriedenstellenden Therapieergebnisse beschäftigen sich viele Studien mit alternativen Therapiemöglichkeiten, unter anderem auch mit Arzneimitteln für neuartige Therapien. Zu diesen zählen auch somatische Zelltherapeutika, wie beispielsweise dendritische Zellen zur adjuvanten Immuntherapie. Um somatische Zelltherapeutika zur Anwendung am Patienten herstellen zu dürfen, muss dem herstellenden Labor durch die zuständige Landesaufsichtsbehörde eine Herstellungserlaubnis erteilt werden. Diese Herstellungserlaubnis wird beim saarländischen Ministerium für Soziales, Gesundheit, Frauen und Familie beantragt und durch dieses erteilt. Zuvor müssen zahlreiche Verfahrensschritte im Herstellungsprozess etabliert sowie validiert werden und Funktionstests mit den generierten dendritischen Zellen durchgeführt werden. Alle hierbei gewonnenen Ergebnisse werden in Form eines Validierungsberichtes der zuständigen Behörde vorgelegt. Ziel dieser Arbeit war es, durch die Etablierung und Validierung unterschiedlicher Methoden zur Erlangung der Herstellungserlaubnis beizutragen. Hierzu wurden verschiedenste Untersuchungen an Proben der DZ-Kulturen durchgeführt, die sowohl Sicherheit als auch Qualität des Herstellungsprozesses und des zellulären Produktes gewährleisten sollen.In 2012 the Institute for Clinical Hemostaseology and Transfusion Medicine of the University of the Saarland started a research project to obtain the permission for the manufacturing of dendritic cells for adjuvant immunotherapy of malignant glioma. Gliomas are the most frequent primary brain tumors and the high-grade glioblastomas account for the largest part of these. The standard course of therapy for high-grade glioblastoma is the combination of operation, radio- and chemotherapy. Under this therapy the mean survival time for a patient amounts to 14,6 month. Due to these poor treatment outcomes, many studies are concerned with alternative therapy approaches for this tumor entity, as for example with Advanced Therapy Medical Products. These also include somatic cell based therapeutics, such as dendritic cells for adjuvant immunotherapy. To be authorized to produce somatic cell based therapeutics for human use the producer has to obtain the permission of manufacturing. This permission is applied at the Ministry for Social Affairs, Health Care, Women and Family of the Saarland. To obtain this permission, numerous procedural steps have to be proved as well as established and performance tests have to be carried out with the manufactured dendritic cells. All results gained at this were submitted to the competent authority in form of a validation report. The object of this research was to contribute to the obtainment of permission for the manufacturing by validation and establishment of different methods. For this purpose different investigations on the dendritic cells were carried out to prove quality and safety of the manufacturing process as well as the manufactured product

Elucidating different pattern of immunoregulation in BALB/c and C57BL/6 mice and their F1 progeny

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .Helminths are large multicellular parasites that infect one quarter of the human population. To prolong their survival, helminths suppress the immune responses of their hosts. Strongyloides ratti delays its expulsion from the gut by induction of regulatory circuits in a mouse strain-specific manner: depletion of Foxp3+ regulatory T cells (Treg) improves the anti-S. ratti immunity in BALB/c but not in C57BL/6 mice. In the current study we compare the hierarchy of immunoregulatory pathways in BALB/c, C57BL/6 mice and their F1 progeny (BALB/c × C57BL/6). Using multicolor flow cytometry, we show that S. ratti induces a distinct pattern of inhibitory checkpoint receptors by Foxp3+ Treg and Foxp3- T cells. Intensity of expression was highest in C57BL/6 and lowest in BALB/c mice, while the F1 cross had an intermediate phenotype or resembled BALB/c mice. Treg subsets expanded during infection in all three mouse strains. Similar to BALB/c mice, depletion of Treg reduced intestinal parasite burden and increased mucosal mast cell activation in S. ratti-infected F1 mice. Our data indicate that Treg dominate the regulation of immune responses in BALB/c and F1 mice, while multiple regulatory layers exist in C57BL/6 mice that may compensate for the absence of Treg.Open Access funding enabled and organized by Projekt DEAL.info:eu-repo/semantics/publishedVersio

A quantitative synthesis study on body mass index and associated factors among adult men and women in Switzerland

Excess weight is caused by multiple factors and has increased sharply in Switzerland since the 1990s. Its consequences represent a major challenge for Switzerland, both in terms of health and the economy. Until now, there has been no cross-dataset overview study on excess weight in adults in Switzerland. Therefore, our aim was to conduct the first synthesis on excess weight in Switzerland. We included all existing nationwide Swiss studies (eight total), which included information on body mass index (BMI). Mixed multinomial logistic regression analyses were performed to assess the associations between different socio-demographic, lifestyle cofactors and the World Health Organization (WHO) categories for BMI. Along with lifestyle factors, socio-demographic factors were among the strongest determinants of BMI. In addition, self-rated health status was significantly lower for underweight, pre-obese and obese men and women than for normal weight persons. The present study is the first to synthesise all nationwide evidence on the importance of several socio-demographic and lifestyle factors as risk factors for excess weight. In particular, the highlighted importance of lifestyle factors for excess weight opens up the opportunity for further public health interventions

Handreichung Anrechnung Teil 1. Ein theoretischer Überblick

Diese Handreichung gibt in neun Kapiteln einen theoretischen Einblick in das Thema Anrechnung. Dabei werden u. a. Anrechnungsverfahren, zentrale Konzepte und Bezugsrahmen sowie die Qualitätssicherung in Anrechnungsprozessen in den Blick genommen. Die Handreichung wird ergänzt durch einen zweiten Teil, der Praxiserfahrungen mit Anrechnung einbezieht. Diese Publikation ist im Rahmen der wissenschaftlichen Begleitung des Bund-Länder-Wettbewerbs „Aufstieg durch Bildung: offene Hochschulen“ entstanden. (Hrgs.

Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein

Background: Proteolytic processing of the prion protein (PrPC) by endogenous proteases generates bioactive membrane-bound and soluble fragments which may help to explain the pleiotropic roles of this protein in the nervous system and in brain diseases. Shedding of almost full-length PrPC into the extracellular space by the metalloprotease ADAM10 is of peculiar relevance since soluble PrP stimulates axonal outgrowth and is protective in neurodegenerative conditions such as Alzheimer’s and prion disease. However, molecular determinates and mechanisms regulating the shedding of PrP are entirely unknown. Methods: We produced an antibody recognizing the neo-epitope of shed PrP generated by ADAM10 in biological samples and used it to study structural and mechanistic aspects affecting the shedding. For this, we investigated genetically modified cellular and murine models by biochemical and morphological approaches. Results: We show that the novel antibody specifically detects shed PrP in cell culture supernatants and murine brain. We demonstrate that ADAM10 is the exclusive sheddase of PrPC in the nervous system and reveal that the glycosylation state and type of membrane-anchorage of PrPC severely affect its shedding. Furthermore, we provide evidence that PrP shedding can be modulated by pharmacological inhibition and stimulation and present data suggesting that shedding is a relevant part of a compensatory network ensuring PrPC homeostasis of the cell. Conclusions: With the new antibody, our study introduces a new tool to reliably investigate PrP-shedding. In addition, this study provides novel and important insight into the regulation of this cleavage event, which is likely to be relevant for diagnostic and therapeutic approaches even beyond neurodegeneration

Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection

Introduction: Transcutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic drug dithranol as novel TCI platform DIVA (dithranol/IMQ based vaccination). In extension of this work, we further optimized DIVA in terms of drug dose, application pattern and established a new IMQ formulation. Methods: C57BL/6 mice were treated on the ear skin with dithranol and IMQ-containing ointments together with ovalbumin-derived peptides. T cell responses were determined by flow cytometry and IFN-ɤ ELISpot assay, local skin inflammation was characterized by ear swelling. Results: Applying the adjuvants on separate skin sites, a reduced number of specific CD8+ T cells with effector function was detectable, indicating that the local concurrence of adjuvants and peptide antigens is required for optimal vaccination. Likewise, changing the order of dithranol and IMQ resulted in an increased skin inflammatory reaction, but lower frequencies of antigen-specific CD8+ T cells indicating that dithranol is essential for superior T cell priming upon DIVA. Dispersing nanocrystalline IMQ in a spreadable formulation (IMI-Sol+) facilitated storage and application rendering comparable immune responses. DIVA applied one or two weeks after the first immunization resulted in a massive increase in antigen-specific T cells and up to a ten-fold increased memory response. Finally, in a prophylactic tumor setting, double but no single DIVA treatment enabled complete control of tumor growth, resulting in full tumor protection. Discussion: Taken together, the described optimized transcutaneous vaccination method leads to the generation of a strong cellular immune response enabling the effective control of tumor growth and has the potential for clinical development as a novel non-invasive vaccination method for peptide-based cancer vaccines in humans